Comparison of Mental Health Resources Used by Patients With Bipolar Disorder Treated With Risperidone, Olanzapine, or Quetiapine

OBJECTIVES: The atypical antipsychotics, risperidone, olanzapine, and quetiapine, have been approved by the U.S. Food and Drug Administration for treatment of mania associated with bipolar disorder. Information on the relative mental health resource use of these therapies is helpful to pharmacy managers since differences in efficacy and safety may translate into differences in mental health care utilization. We compared charges for other mental health services associated with risperidone, olanzapine, and quetiapine treatment of patients with bipolar disorder to assess whether there were significant differences between these therapies. A secondary analysis involved dose-equivalent adjustment of the average allowed charge of the 3 atypical antipsychotics. METHODS: This was a retrospective study based on administrative data for 46 U.S. commercial health plans represented in a commercial database covering the period January 1998 through April 2002. The 6,625 patients included in the study had at least 2 contiguous pharmacy claims for a study antipsychotic, had received no other antipsychotics concurrently, and had not switched from an alternative antipsychotic in the preceding 90 days. Provider-submitted (billed) charges were selected in preference to paid amounts as being more accurate indicators of relative differences in the use of mental health resources. Mental health care charges were measured per patient per month (PPPM) and included charges for the study antipsychotics and charges for the other mental health care services (inpatient, physician and other ambulatory, and other psychotropic medications). Differences in other mental health care charges PPPM among the 3 therapies were assessed with multivariate regression, adjusting for differing patient characteristics. Differences in antipsychotic drug charges PPPM were assessed after adjustment to reflect an equivalent average daily dose. RESULTS: Regression estimates adjusted for patient differences did not show statistically significant differences in other mental health care charges PPPM among the 3 antipsychotic drug therapies. Other mental health charges associated with quetiapine were estimated to be $14, or 3% lower than those associated with risperidone, but this difference was not statistically significant (P=0.069). The PPPM charges for quetiapine versus olanzapine and olanzapine versus risperidone were also not different (P=0.231 and P=0.39, respectively). After adjusting for differences in average daily dose, risperidone and quetiapine had antipsychotic drug charges that were $84 and $76 PPPM lower than those of olanzapine (P less than0.01); the difference between the adjusted drug charges PPPM for risperidone and quetiapine was not significant. CONCLUSIONS: Total charges for mental health services other than the study drug were not different for risperidone, olanzapine, and quetiapine in patients treated for bipolar disorder. However, based on prescription charges, olanzapine appears to be considerably more costly at an equivalent daily dose than either risperidone or quetiapine.

The goal of our study was to compare, within a large patient population, the mental health resource use associated with 3 atypical antipsychotics, risperidone, olanzapine, and quetiapine, in the treatment of patients with bipolar disorder. The PharMetrics Patient-Centric Database was chosen for this purpose. 33 At the time of this study, the PharMetrics database contained administrative data for 27 million patients from 46 commercial health plans located throughout the United States. Nearly 78,000 patients (0.3%) had at least 1 medical claim for bipolar disorder, with a relatively small proportion of these having used any of the study antipsychotics and having met other criteria for inclusion. The analysis focused only on patients who did not switch from a prior antipsychotic and who were not treated concurrently with multiple antipsychotics. Patients who failed on a prior antipsychotic, because of ineff i c a c y or side effects, were assumed to be more treatment re s i s t a n t , placing the switched-to therapy at a disadvantage. The re q u i re m e n t of antipsychotic monotherapy provided for a cleaner comparison. Mental health re s o u rces were associated with risperidone, olanzapine, and quetiapine according to defined "treatment episodes" with each atypical antipsychotic.

Inclusion Criteria
Although the PharMetrics data extract covered the period January 1998 through April 2002, only antipsychotic treatments beginning in 1999 were compared. The year 1998 was excluded from these comparisons because this period covered the early adoption phase of quetiapine (approved by the FDA on September 26,1997); therefore, exclusion of these earlier data placed quetiapine on a more equal footing with risperidone and olanzapine. So that preexisting health states could be assessed, treatment episodes were required to have patient health plan enrollment for at least 90 days prior to initiation of each treatment. Bipolar disorder was identified with I n t e rnational Classification of Diseases, 9th Revision, Clinical M o d i f i c a t i o n (ICD-9-CM) codes 296.4-296.8 appearing on either outpatient or inpatient claims.
At the time of this study, risperidone, olanzapine, and quetiapine had FDA indications for schizophrenia only but were also frequently used for bipolar disorder, major depression, and dementia. Of patients who had claims reporting any of these other conditions along with bipolar disorder at or near the time of treatment (about 5% of patients), classification as bipolar required that the diagnosis code for bipolar (a) be the most recent diagnosis and (b) appear on at least half of the claims. This minimized the chances of including patients who re c e i v e d antipsychotic treatment primarily for conditions other than bipolar d i s o rd e r. Other mental disorders were not considered to be a likely basis for antipsychotic treatment though they could be related to the treated condition or to the treatment itself (e.g., drug dependence and abuse, and sexual, sleep, and eating disorders).
To be included in the study, each patient also must have had at least 2 contiguous prescriptions (typically 30 days supply per prescription) of risperidone, olanzapine, or quetiapine, thus excluding patients with single prescriptions that may or may not have been fully used. In addition, only patients who received antipsychotic monotherapy treatment with any of the 3 antipsychotics and had not switched from an alternative antipsychotic in the previous 3 months were included. These inclusion criteria were intended to reduce selection bias and enable comparison among a more homogenous patient population. E ffects of inclusion criteria on the number of antipsychotic treatment episodes ultimately included in the study are shown in Table 1.

Assessment
The unit of observation was the antipsychotic "treatment episode." A treatment episode was identified as a distinct sequence of 2 or more prescriptions for a specific antipsychotic. To qualify as the first prescription in a treatment episode, a gap of at least 90 days in prescriptions for that antipsychotic was required beforehand. Gaps of less than 90 days were allowed within a treatment episode. Larger gaps resulted in a second treatment episode with the same antipsychotic if the gap was followed by another sequence of 2 or more prescriptions. The final date of a treatment episode was normally calculated as the date on which the last pre s c r i p t i o n ' s days supply was exhausted. However, in those cases where patient disenrollment from the health plan or the end date of the data preceded this calculated date, the disenrollment date or the data end date became the final date of treatment. Mental health services associated with each of the 3 atypical antipsychotics were measured within treatment episodes.
Three possible dollar measures for gauging service use n o rmally appear on medical claim forms: billed charg e s , allowed charges, and paid amounts. The PharMetrics data at the time of this study contained billed charges and paid amounts but not allowed charges. Although billed charges overstate costs, they were chosen as the preferred measure of health resource use because they were judged to more accurately m e a s u re re l a t i v e d i ff e rences between patients and patient groups. Paid amounts, unlike billed charges, reflect coverage levels (copayments, deductibles, and benefit limits), which are particularly relevant to mental health care and can vary considerably between health plans and lines of business within health plans-this is particularly important when aggregating data across several health plans. Additionally, paid amounts may be minimal or zero when another insurer is the primary payer and a re often unre p o rted when the method of provider payment is capitation. Allowed amount is also affected by benefit limits, other p r i m a ry payers, and capitation and, for this reason, even if available, might also be considered inferior to billed charges for purposes o f measuring relative diff e rences in health re s o u rce use. 34 The primary measure assessed in this study was mental health care charges exclusive of antipsychotic drug charges. This measure is termed "other mental health care charges" and includes charges reported on all medical or hospital claims with mental disorder primary diagnoses (ICD-9-CM 290.xx-316.xx) and all prescription claims for psychotropic medications other than the reference antipsychotic. Secondary diagnoses, which were reported for a small proportion of claims, were ignored. The medical component of other mental health care charges includes inpatient hospital, physician office, and other ambulatory while the prescription component includes mood stabilizers, antidepressants, anxiolytics, hypnotics, and anticholinergics. Antipsychotic drug charges were assessed separately.
Other mental health care charges and antipsychotic drug charges were measured per patient per month (PPPM) to permit meaningful comparisons since the duration of antipsychotic treatment episodes varied. Treatment durations were affected by patient disenrollment and the end date of the data as well as by natural terminations, which could not be easily interpreted as treatment failures (see Discussion).
Mental health care charges during the 90 days preceding the beginning of each treatment episode were used as the principal marker for patient illness severity. Capture of records from prior periods longer than 90 days was limited by data availability and its effect on reducing sample size. As shown in Table 1, the 90-day re q u i rement itself resulted in a nearly 20% loss in sample size. Longer prior periods would have resulted in disproportionately larger percentage losses. The 90-day period was considered to be appropriate also because time periods further removed from treatment episodes would be less indicative of health states at time of treatment.
Medical and prescription charges with service or fill dates falling within a treatment episode were assigned to that episode, with the exception of inpatient hospital services. Only hospitalizations beginning within a treatment episode were assigned to that episode, since preceding circumstances triggered hospitalizations beginning before, but extending into, an episode. Unfortunately, precise measurement of treatment episodes was not possible for individuals who initiated or terminated one of the atypical antipsychotics during a hospital stay because details of inpatient pharmacy utilization are not included in hospital claims.

Statistical Analysis
Mental health care charges PPPM associated with risperidone, olanzapine, and quetiapine treatment episodes were first compared without controlling for patient differences. While they provide a first approximation, these unadjusted comparisons a re unreliable because they can be influenced by diff e re n c e s in illness severity and other patient characteristics that affect mental health resource use.
In the analysis of other mental health care charges, ordinary least squares multivariate regression was used to adjust for patient differences. Because they have highly skewed distributions, patient-level health care data are typically transformed into logarithms to achieve more normal distributions before being subjected to statistical estimation and testing. 35 This procedure was applied to other mental health care charges. The estimated effects of the antipsychotic drugs and patient characteristics, which were in logarithmic form, were reconverted to actual values that show the incremental (per unit) effect of each variable (e.g., 1 year of age). Explanatory variables included in the re g ression model are described in detail in Table 2. Risperidone, olanzapine, and quetiapine were specified as binary (1,0) variables in the regression model. Since one of the antipsychotics must be excluded as the default, to enable comparison of all antipsychotic pairs, the re g ression was reestimated alternating the default.
Unadjusted (actual) drug charges PPPM may not accurately reflect price differences among the antipsychotic therapies if average daily doses differ. Average daily doses may vary if patients differ with respect to the amount needed for therapeutic e ffect. For example, more severely ill patients may re q u i re higher doses, while females and children, because of lesser body weight, may require lower doses. Average daily doses will also v a ry if patients are more or less compliant in filling pre s c r i p t i o n s .
T h e re f o re, drug price comparisons were made after adjustment of the average drug charges PPPM to reflect equivalent average milligrams per day. This adjustment was complicated by the fact that risperidone, olanzapine, and quetiapine have different milligram scales.
In the first step of the adjustment, olanzapine and quetiapine milligrams were converted to risperidone equivalents. This was done by calculating for each of the 3 antipsychotics the average of the mean daily doses for the bottom and top tenth of each daily dose range and then dividing the olanzapine and quetiapine averages into the risperidone average to create weights (overall mean daily doses for each antipsychotic were not used to calculate weights because they are more sensitive to case mix and prevailing prescribing practices). Actual milligrams per day of olanzapine and quetiapine were multiplied by these weights to create risperidone equivalents. One milligram of risperidone was equivalent to 3.8 milligrams of olanzapine and to 91.7 milligrams of quetiapine. Average daily doses of olanzapine and quetiapine, c o n v e rted to risperidone-equivalent milligrams, were adjusted to equal the average daily dose of risperidone. In the second step, olanzapine and quetiapine drug charges PPPM were adjusted u p w a rd or downward in accordance with the upward or downw a rd adjustment in risperidone-equivalent milligrams.

Number of Treatment Episodes With Risperidone, Olanzapine, and Quetiapine After Application of Each Inclusion Criterion
Published dose equivalents such as chlorpro m a z i n eequivalents 36 were not used because they are based on clinical data (minimal effective dose) that may not reflect doses used in actual practice. For example, the data for this study revealed that the majority of quetiapine-treated patients with bipolar disorder had doses that fell below the recommended (see Physicians' Desk Refere n c e) range of 150 mg/day-750 mg/day. The method used here has been used in other studies. [37][38][39]

■ ■ Results
A total of 6,625 unique patients accounted for 7,518 treatment episodes for bipolar disorder that met the criteria for inclusion (Table 1). Approximately 10% of patients had multiple episodes falling within the study period in that they were treated at different times with the same or with 2 or all 3 of the antipsychotics. For the period January 1999 through April 2002, there were 2,925 treatment episodes with risperidone (2,698 patients), 3,333 with olanzapine (3,102 patients), and 1,260 with quetiapine (1,175 patients). (The total number of patients is greater than 6,625 because the same patient may appear in more than one antipsychotic group.) Table 3 compares characteristics of patients with a bipolar diagnosis treated with risperidone, olanzapine, or quetiapine. These characteristics were specified in the regression model to control for differences in other mental health care charges PPPM that might be unrelated to the antipsychotic treatment. The 3 antipsychotic groups differed significantly with respect to age, sex, and type of bipolar disorder. Among the markers for mental illness severity, prior mental health care charges PPPM did not differ significantly among the 3 groups. However, the quetiapine group had significantly more prior prescriptions for psychotropic medications of all types than did the risperidone and olanzapine groups, suggesting more difficulty in controlling the symptoms of mental illness. The olanzapine and quetiapine groups were treated with significantly (or nearly significantly) Reference atypical antipsychotic treatment. Effects on other mental health care charges of treatment with each of the atypical antipsychotics (risperidone, olanzapine, and quetiapine) were captured by 2 binary variables specifying 2 of the antipsychotics with a zero value for both indicating the third.

Explanatory Factors Explored in the Regression Analysis
Age and sex. Age was specified as a continuous variable, sex as a binary variable (1 for a male).
Type of bipolar disorder. Patients were grouped according to the most frequent bipolar manifestation re c o rded on their medical claim form ("manic," "depressed," "mixed," "unspecified"). Three binary variables indicated "manic," "depressed," and "mixed" manifestations, while a zero value for each variable indicated "unspecified." Previous nondrug mental health care charges. Values of the dependent variable reported during the 3 months before a treatment episode were used as a proxy for illness severity and other undefined patient characteristics.

Number of previous prescriptions for psychotropic drugs.
The number of prescriptions for psychotropic medications during the 3 months preceding the treatment episode can be indicative of the degree of patient difficulty in controlling the symptoms of mental illness.
Reference atypical antipsychotic dose. Since the atypical antipsychotic drug charges are not a component of other mental health care charges, dose levels were used as an additional proxy for illness severity. It was assumed that more symptomatic patients required higher atypical antipsychotic doses. Because this measure is contemporaneous with the mental health care charges being assessed, atypical antipsychotic dose level may have an advantage over estimates of previous mental health care charges in indicating illness severity. 35 To enable comparisons between the 3 antipsychotics (which have different therapeutic dose scales), olanzapine and quetiapine milligrams were converted to risperidone equivalents (see Methods).
Nonmental health care charges per patient per month (PPPM). This variable reflects the impact of other patient morbidities present during treatment for bipolar disorder, which might affect mental health resource consumption.
Substance dependence. Patients with bipolar disorder who also have alcohol or drug dependence/abuse might be more difficult to treat resulting in greater mental health care use. 4 2 , 4 3 A single binary variable captured substance dependence/abuse (ICD-CM-9 codes 291.xx, 292.xx, 304.xx, 305.xx).

Treatment-episode length.
Because about 50% of treatment episodes were censored (by end point of data or patient disenrollment) and because treatment duration can also be influenced by illness severity, this variable was assumed to be largely exogenous to the specific antipsychotic treatment. Because of the time required to stabilize patients, other mental health care charges PPPM were hypothesized to have a negative association with episode length (months).

Time of treatment.
Treatment episodes were not uniform in calendar time.
To control for health care price and utilization trends, a variable that measured the time (months) between the midpoint of each treatment episode and the last s e rvice date for the study (4/30/02) was specified. An increasing trend corresponds with a negative parameter estimate, while a positive estimate indicates a declining trend.
Type of coverage. The commercial health plans had several lines of business ("health maintenance organization," "indemnity," "point of service," "preferred provider organization," and "other"), which might affect health care prices and utilization controls, ultimately affecting billed charges. Four binary variables indicated the specified categories, while zeroes for all of these variables indicated "other." higher antipsychotic doses than the risperidone group, also suggesting greater illness severity. Based on other health care expenses, the quetiapine group appears to have been generally less healthy than the risperidone and quetiapine groups. Substance abuse/dependence was significantly more prevalent in the olanzapine and quetiapine groups than in the risperidone gro u p .
Risperidone treatment episodes were significantly longer than olanzapine and quetiapine episodes and occurred earlier.
Olanzapine episodes also occurred earlier than quetiapine episodes. Some of the differences in mental health charges PPPM may be caused by changes over time in mental health care prices and service utilization during the 1999-2002 period of this study. The 3 antipsychotic groups also differed significantly in type of health care coverage and geographic location, characteristics that could also be associated with differing health care prices and service utilization.  Table 4. Mental health care charges PPPM were highest for olanzapinetreated patients and lowest for quetiapine-treated patients. The much higher charges associated with olanzapine treatment were l a rgely due to the substantially higher charges for the medication itself. The other mental health care charges of olanzapine-tre a t e d patients fell between those of risperidone and quetiapine, which had the lowest. For all 3 treatment groups, inpatient charges accounted for the largest portion of other mental health care charges followed by physician office and other ambulatory services. Charges for other p s y c h o t ropic drugs were highest for quetiapine. Whereas mood stabilizers have been the principal therapy for bipolar disorder and may be used with other medications as adjunctive therapy, a more detailed comparison between these and the antipsychotics used by the patient groups is warr a n t e d .

Characteristics of Patients With a Bipolar Diagnosis Treated With Risperidone, Olanzapine, or Quetiapine, Monotherapy and Who Were Not Switched From a Prior Antipsychotic
In Table 5, average days supply PPPM is reported along with average charges PPPM for the other psychotropic medications also used by bipolar patients during treatment with risperidone, olanzapine, or quetiapine. Average days supply and charges PPPM are also shown for the 3 antipsychotics. Days supply PPPM close to 30 for the antipsychotics does not necessarily reflect a high degree of treatment compliance. Changes in pill strength may have resulted in some prescriptions being not fully used. Regardless, use of other psychotropic medications was relatively minor. Antidepressants were the most frequently used category of other psychotropic medication, followed by anxiolytics and then mood stabilizers.

Multivariate Regression Results
The unadjusted mental health care charges reported in Table 4 reflect the influences of patient characteristics as well as the effects of the antipsychotic therapies. Regression estimates adjusted for patient differences (Table 6) did not show statistically significant differences in other mental health care charges PPPM among the 3 antipsychotic therapies. Charges associated with quetiapine were estimated to be $14 or 3% lower than those associated with risperidone, but this difference was not statistically significant (P = 0.069). The estimated $9 or 2% lower charges for quetiapine versus olanzapine and the estimated $5 or 1% lower charges for olanzapine versus risperidone were also not different (P = 0.231 and P = 0.39, respectively). These estimates were calculated relative to the mean of other mental health care charges for the study population as a whole: $526 PPPM. With logarithmic estimation, percentage differences are the same irrespective of the charge level used as the base for re t r a n s f o rmation to actual values. Absolute diff e rences, however, are sensitive to the base.
The unadjusted differences between treatment groups are largely explained by other statistically significant factors that were specified in the model. Charges PPPM declined with patient age and were somewhat lower for men than women. The charges PPPM for patients with unspecified manifestations of bipolar disorder were similar to those for patients with manic symptoms and tended to be lower than those for depressed or mixed manifestations. Higher levels of mental health resource use prior to treatment with risperidone, olanzapine, or quetiapine p redicted higher levels during treatment as did a higher number of previous prescriptions for psychotropic medications. Patients with a bipolar diagnosis, who were also afflicted with other morbidities as reflected in nonmental health care charges PPPM, also had slightly higher levels of mental health resource use. Substance dependence had the largest impact on mental health care resource consumption, increasing it by $228 PPPM (43%). Treatment-episode length had a negative association with other mental health care charges PPPM, perhaps reflecting an association between longer continuity and greater efficacy and tolerability. There was a declining trend in these charges during the study period, as reflected in the positive value of "time of treatment." All of the specified coverage types were associated with significantly higher mental health care charges PPPM than the less common miscellaneous types, with the most managed type (HMO) having the lowest charges and the least managed (indemnity) having the highest. Geographic location also showed the expected patterns, with significantly lower mental health care charges in the South compared with other regions of the United States. The high F-ratio and the re s p e c t a b l e a d j u s t e d R 2 (for cross-sectional analyses of individual level, health care financial data) show that the model fits the data reasonably well.

Adjusted Antipsychotic Drugs Charges
While risperidone, olanzapine, and quetiapine did not differ significantly in their effects on other mental health care charges in the treatment of bipolar disorder, antipsychotic drug charges d i ff e red considerably (Table 4). Patients assessed during olanzapine treatment episodes had the highest antipsychotic drug charges PPPM, with those assessed during risperidone or quetiapine treatment episodes having considerably lower drug charges. However, these differences only partly reflect differences in drug prices. Differing drug quantities or average daily doses also affected antipsychotic drug charges PPPM. In Table 7, the effects of differences in average daily dose were removed by first converting quetiapine and olanzapine doses to risperidoneequivalent milligrams and then adjusting quetiapine and olanzapine drug charges upward or downward to reflect the same average dose per day of treatment (2.1 mg) inherent in risperidone drug charges. This adjustment reduced olanzapine' s charges from $275 to $231 PPPM and quetiapine' s from $171 to $156 PPPM versus $147 PPPM for risperidone. The adjusted average allowed allowed charge for olanzapine was greater than the average allowed charge for either risperidone or quetiapine (P < 0.01 for both comparisons), while the adjusted average allowed charge was not different between quetiapine and risperidone (P = 0.15).

■ ■ Discussion
The clinical literature has shown risperidone, olanzapine, and quetiapine to be effective in the treatment of bipolar disorder as both monotherapy and adjunctive therapy.  Clinical comparisons between risperidone and olanzapine have yielded mixed results, while, to our knowledge, there have been no direct comparisons involving quetiapine. One study comparing mental health resource use between the 3 atypicals in the treatment of bipolar disorder found risperidone to have lower costs than olanzapine while differences with quetiapine were not statistically significant. 32 However, this previous research involved very small patient numbers and did not control for differences in patient or treatment characteristics.
Our study further investigated diff e rences in other mental health resource use associated with risperidone, olanzapine, and quetiapine treatment for bipolar disorder. Comparisons were limited to patients treated with one or another of these antipsychotics who did not have evidence of having switched from another antipsychotic in the preindex period or use of another antipsychotic concurrently. Temporary concurrent use often occurs when switching from one antipsychotic to another, 3 9 and simultaneous treatment with multiple antipsychotics over long periods is not uncommon. By imposing these re q u i re m e n t s , we provided a more homogenous patient population, thus allowing for more reliable comparisons. To illustrate, of the treatment episodes excluded, patients treated with quetiapine w e re 2 to 3 times more likely than those treated with risperidone or olanzapine to have switched from a previous antipsychotic, with a higher pro p o rtion involving concurrent use than risperidone and olanzapine. This may reflect a greater tendency for practitioners to have used quetiapine as a second-line therapy, or it may reflect its later entry to the U.S. market-in October 1 9 9 7 -c o m p a red with risperidone (January 1994) and olanzapine (October 1996).
Unadjusted comparisons showed other mental health care charges PPPM to be similar for risperidone, olanzapine, and quetiapine. Additional comparisons of other mental health care charges were undertaken with multivariate regression. The results of regression estimation that controlled for differences in patient age, sex, type of bipolar manifestation, illness severity (gauged by multiple indicators) and other patient characteristics showed no significant differences in other mental health care charges PPPM among the 3 study drugs. Quetiapine's diffe re n c e f rom risperidone was the largest (-$14 PPPM or -3%) but was not statistically significant (P = 0.069). Estimated diff e rences between olanzapine and risperidone (-$5, -1%) and olanzapine and quetiapine ($9, +2%) were smaller and also not statistically significant (P = 0.39 and P = 0.23, re s p e c t i v e l y ) . Most of the other e x p l a n a t o ry factors specified in the model were statistically significant and predicted as anticipated. Substance dependence (or abuse) was the single most important factor explaining patient d i ff e rences in other mental health care charg e s . This study did not consider effects of risperidone, olanzapine, and quetiapine on the mental health resource use of patients after discontinuation of each treatment. Only mental health resources used within the confines of each treatment episode were compared. A more comprehensive assessment may have c o n s i d e red the effects of treatment failure on subsequent mental health re s o u rce use. In another study (yet unpublished) utilizing the same database, we examined the reasons for antipsychotic treatment discontinuation among bipolar patients, finding that not all discontinuations can be interpreted as treatment failure. Nearly 50% of treatment episodes were censored because of patient disenrollment or the end point of the data. Among the remainder who were observed for 4 months after treatment discontinuation, 14% of patients in all 3 therapy groups switched to another antipsychotic (clear treatment failure); 44% of risperidone, 48% of olanzapine, and 49% of quetiapine patients switched to other psychotropic medications only (treatment failure or abatement of symptoms requiring antipsychotic therapy); and 39% of risperidone, 35% of olanzapine, and 34% of quetiapine patients switched to no psychotropic medications whatsoever (no need for maintenance therapy of any kind or total noncompliance). Small percentages of patients within each group returned to the same antipsychotic after a hiatus of at least 3 months of no psychotropic drug use. These unpublished data do not indicate that treatment failure was more prevalent in one group than another, which is consistent with the findings of the present study in which there were no significant diff e rences in other mental health re s o u rce use during t reatment. One might expect medications that were less eff e c t i v e to be associated, after adequate adjustment for disease severity, with both higher mental health resource use during treatment and higher rates of discontinuation due to drug therapy failure.
While risperidone, olanzapine, and quetiapine did not differ significantly in their effects on total other mental health resource use, olanzapine had considerably higher average drug charges than risperidone or quetiapine. After daily doses were standardized, olanzapine drug charges PPPM exceeded those of risperidone and quetiapine by 57% and 49%, respectively (significant at P < 0.01), while the smaller difference between risperidone and quetiapine was not statistically significant (P=0.15). Differences in drug prices may influence choice of the  3 antipsychotics for treatment of bipolar disorder in addition to consideration of total other mental health re s o u rce utilization and cost. Our findings of no significant difference in other mental health resource use between the most commonly prescribed atypical antipsychotics among bipolar patients are timely and relevant in today' s cost-conscious environment. Given the high acquisition costs and recent increase in use of atypical antipsychotics, clinical and economic data that can aid managed care decision makers and physicians in choosing between the diff e re n t products on the market are useful. Because of the sensitive n a t u re of mental health conditions, the decision-making p rocess should incorporate factors such as prior clinical response to any one particular antipsychotic medication and each medication' s side effect profile. 40 Given that there is no evidence that any one atypical antipsychotic is superior in terms of efficacy, tolerability and patient acceptability are important issues that should help guide the treatment decision. Poor symptom control and side effects can translate into noncompliance and increased contacts with the medical system, potentially significant cost drivers.

Limitations
The results of the present study need to be considered within the context of the inherent limitations of the data source (i.e., an administrative claims data). While reliance on medical claims is a common and acceptable practice in these types of studies of resource consumption, the assumption is that cases selected for analysis are in fact suffering from the condition of interest. Miscoding and improper diagnosis on the part of the physician are possibilities that warrant consideration. Moreover, additional assumptions are required when identifying which medications are being prescribed for which conditions.
The use of treatment episodes as the unit of analysis pro v i ded the opportunity to attribute other mental health resource use to the appropriate medication; however, certain limitations of this approach need to be acknowledged. The precise measurement of treatment episodes was not possible for individuals who initiated or terminated one of the atypical antipsychotics during a hospital stay because details of inpatient pharmacy are not included in hospital claims. The fact that approximately 10% of patients had multiple treatment episodes may have contributed to interdependence of sampling units, though this is mitigated by the fact that the same patients were observed at different times and under different circumstances. Interdependence of sampling units can result from other factors, such as different patients being treated by the same physician, and exclusion of some observations (treatment episodes) to avoid interd e p e n d e n c e can itself create other bias.
Another methodological issue that might affect the interpretation of this study' s findings is the conversion of actual costs into log values for the purpose of regression estimation. Log transformation of cost (charge) values is a standard procedure to avoid inaccurate statistical testing and mitigate the influence of e x t reme outliers. 3 5 H o w e v e r, in pharmacoeconomic comparisons, this pro c e d u re can lead to understatement of cost diff e re n c e s when the cost distributions being compared have dissimilar variances, 41 which may have been the case here.

■ ■ Conclusion
Based on data from several commercial health plans and after adjustment for patient differences, there appears to be little difference in other mental health resource use associated with risperidone, olanzapine, and quetiapine treatment of patients with bipolar disord e r. However, olanzapine had a higher average allowed drug charge PPPM than either risperidone or quetiapine when adjusted for equivalent average daily dose; the adjusted average allowed charge PPPM was not diff e rent between risperidone and quetiapine.  Differences between olanzapine and risperidone and between olanzapine and quetiapine are significant at P <0.01. Difference between risperidone and quetiapine is not significant (P = 0.15). Antipsychotic drug charges divided by the ratio of risperidone, olanzapine, or quetiapine risperidone-equivalent mg/day to risperidone mg/day equivalents. PPPM = per patient per month.